Methods of amination

ABSTRACT

A method of synthesizing a compound of formula I: comprising the step of reacting a moiety of formula II: with a moiety of formula III: in compressed carbon dioxide in the presence of a transition metal catalyst and a base, wherein L is a labile leaving group; R N1  is optionally substituted C 5-20  aryl; R N2  is selected from optionally substituted C 5-20 aryl, optionally substituted C 3-20  heterocyclyl, optionally substituted C 3-7  alkyl, and optionally substituted sulfonyl; R N3  is selected from H and optionally substituted C 1-7  alkyl, C 3-20  heterocyclyl and C 5-20  aryl; or R N2  and R N3  together with the nitrogen atom to which they are attached form optionally substituted nitrogen-containing C 3-20  heterocylyl or C 5-20  heteroaryl; and R 1  R 2  and R 3  are independently selected from optionally substituted C 1-7  alkyl, C 5-20  aryl, C 3-20  heterocyclyl, hydroxy, halo, amino and C 1-7  alkoxy, or two of R 1 , R 2  and R 3 , together with the silicon atom to which they are attached, may form a silicon containing C 5-7  heterocyclyl group.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a national stage filing under 35 U.S.C. 371of International Application No. PCT/GB2005/001130, filed on Mar. 18,2005, which claims foreign priority benefits to United KingdomApplication No. 0406125.5, filed Mar. 18, 2004.

The present invention relates to methods of amination, and in particularto methods of aminating aromatic groups using transition metalcatalysis.

Amine derivatives are exceptionally important pharmaceuticalintermediates and active ingredients in many drugs. Aromatic amines formthe basis of the modern organic-based photoconductors in xerography(photocopiers and photoconductors) [References 1-4], solar cells and ashole transporting materials in organic and polymeric light emittingdevices [References 5-11].

Supercritical carbon dioxide and compressed carbon dioxide have emergedas a general environmentally benign solvent for the synthesis of organicmolecules [References 12 and 13] and polymers [Reference 14]. It can beparticularly beneficial in a variety of palladium-mediated syntheses andcross coupling reactions [References 15-18] and for the integration ofsynthesis with processing. Particular examples of use in organicelectronic materials are described by Ober and DeSimone [References19-22]. Opportunities for the controlled deposition of organic andpolymeric electronic materials have been disclosed [Reference 23].Deposition from compressed CO₂ will allow the controlled supramolecularordering of materials owing to the ability to control demixing ofsamples during deposition from CO₂ solutions.

Amination reactions have been historically developed using the Ullmanncoupling procedure [References 24 to 27], which involves thecopper-mediated coupling of aryl halides and aryl 4-toluenesulfonates.More recently a family of palladium catalysed aromatic aminationreactions have been developed in which an aryl halide or aryl tosylateis typically coupled with an amine derivative in the presence of apalladium (0) catalyst, a suitable bulky organophosphine ligand and abase [Reference 28]. The scope and methodology of such a procedure (the‘Buchwald-Hartwig’ amination reaction) has been reviewed by Buchwald andHartwig [References 29-31] and forms the basis of a wide variety ofamine syntheses. The use of these methods for the manufacture ofelectroactive polymers has been described [Reference 32].

There is an attraction in combining the synthesis of aminederivativesand the subsequent processing in compressed CO₂. Advantages couldinclude an environmentally friendly manufacturing process plus controlof morphology of the final product using anti-solvent techniques (see A.I. Cooper's review [Reference 14]) for pharmaceuticals. In theelectroactive organic and polymeric materials arena an advantage ofintegrated synthesis and processing will lead to architecturallycontrolled multilayered devices with supramolecular order. A particularexample is the use of blended materials to improve organic LED deviceperformance [Reference 33]. Another example of the benefit of anintegrated synthesis and processing system is the advantage of polymerdeposition where layer separation is required, by virtue of theimmiscibility of the deposition solvent with the first layer, orinduction of microphase segregation of two materials co-deposited fromcarbon dioxide whose solubility difference can be exploited to generateorganised and phase segregated materials. This feature has specificadvantages in organic photovoltaic devices [Reference 34].

Although palladium catalysed carbon-carbon bond formation reactions insupercritical CO₂ have been described [Reference 36], prior art in thefield would suggest that carrying out the palladium catalysed aminationreaction in compressed CO₂ (the Buchwald-Hartwig amination reaction)would fail because it is well known that amines form carbamic acids inthe presence of carbon dioxide. In fact, the formation of a carbamicacid has been used to suppress the reactivity of a free aminosubstituent in the course of a synthesis in compressed carbon dioxide[Reference 35].

The present inventors have now discovered that palladium catalysedamination reactions can be carried in compressed CO₂ by the use ofselected N-silylamines.

Accordingly, the present invention provides a method of synthesizing acompound of formula I:

comprising the step of reacting a moiety of formula II:R^(N1)-L (II)with a moiety of formula III:

in compressed carbon dioxide in the presence of a transition metalcatalyst and a base, wherein:

L is a labile leaving group;

R^(N1) is optionally substituted C₅₋₂₀ aryl;

R^(N2) is selected from optionally substituted C₅₋₂₀ aryl, optionallysubstituted C₃₋₂₀ heterocyclyl, optionally substituted C₃₋₇ alkyl, andoptionally substituted sulfonyl;

R^(N3) is selected from H and optionally substituted C₁₋₇ alkyl, C₃₋₂₀heterocyclyl and C₅₋₂₀ aryl; or

R^(N2) and R^(N3) together with the nitrogen atom to which they areattached form optionally substituted nitrogen-containing C₃₋₂₀heterocylyl or C₅₋₂₀ heteroaryl; and

R¹, R² and R³ are independently selected from optionally substitutedC₁₋₇ alkyl, C₅₋₂₀ aryl, C₃₋₂₀ heterocyclyl, hydroxy, halo, amino andC₁₋₇ alkoxy, or two of R¹, R² and R³, together with the silicon atom towhich they are attached, may form a silicon containing C₅₋₇ heterocyclylgroup (e.g. silacyclobutyl).

R^(N1) and R^(N2) may be linked by a single bond, such that the compoundof formula I comprises a nitrogen-containing C₅₋₇ heterocyclyl orheteroaryl group formed from R^(N1) and R^(N2), and the nitrogen towhich they are attached.

It has also been found that these reactions proceed more efficientlythan when carried out in an organic solvent, such as toluene.

Compressed Carbon Dioxide

The term “compressed carbon dioxide” means herein carbon dioxide whichhas been compressed under pressure to produce liquid carbon dioxide orsupercritical or near supercritical carbon dioxide.

A fluid is termed “supercritical” when its temperature exceeds thecritical temperature (Tc). At this point the two fluid phases, liquidand vapor, become indistinguishable [Reference 37]. The criticaltemperature of carbon dioxide is 31.1° C. and the critical pressure 73.8bar. Conditions and solvent media required to form supercritical or nearsupercritical states are described in Reference 12 and References 38 to45.

The reaction is preferably carried out at a pressure between 800 psi and4000 psi. More preferably the reaction pressure is greater than, orequal to, 1500 psi. The reaction is also more preferably less than, orequal to, 3500 psi.

Transition Metal Catalyst

Suitable transition metal catalysts include complexes of platinum,palladium, iron, nickel, ruthenium and rhodium. Catalyst complexes mayinclude chelating ligands, such as, by way of example only, C₁₋₇ alkyland C₅₋₂₀ aryl derivatives of phosphiones and bisphosphines, imines,arsines and hybrids thereof, including hybrids of phosphines withamines.

Additionally, heterogeneous catalysts containing forms of these elementsare also suitable as catalysts for the present invention. Catalystscontaining palladium and copper are preferred, with palladium basedcatalysts being more preferred.

The active form of the transition metal catalyst is not wellcharacterised. Therefore, the term “transition metal catalyst” as usedherein refers to any transition metal catalyst and/or catalyst precursoras is introduced into the reaction vessel and which is, if necessary,converted into the active phase, as well as active form, of the catalystwhich participates in the reaction.

The palladium catalysts most suitable for use in the present inventionare formed from palladium(II) salts and appropriate ligands, preferablyphosphine ligands. Such catalysts are known in the art and are describedin Reference 12, 36, 38-45. Particularly preferred catalysts include Pdcatalysts with one or more phosphine ligands such as PPh₃, P(C₆H₁₂)₃,2-diphenylphosphinophenol, binap, dppf, P(t-Bu)₂(biphen) where biphenrepresents 2-phenyl-phen-1-yl, where the 2-phenyl group may bear at oneor more of the 2′,4′ and 6′-positions iso-propyl groups or N,N-dimethylamino groups. Examples of catalysts include, but are not limited to,those derived from Pd(II) acetate (especially with P(t-Bu)₂(biphen)ligands, where biphen is as defined above), Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂ andPd(dppf) Cl₂.

Other preferred transition metal (preferably palladium) catalysts arethose based on the N-heterocyclic carbenoid ligands described forexample by Nolan [Reference 46], and the micro-encapsulated transitionmetal catalysts disclosed in Reference 36.

The transition metal catalyst is preferably present in the range of0.001 to 20 mol %, and preferably 1.0 to 2.5 or 5 mol %, with respect tothe moiety of formula II.

Base

Suitable bases for use in the present invention include bases of group 1metals, carbonate, phosphate or tert-butoxy/phenoxy bases and superbases[References 47 and 48]. Preferred bases are group 1 metal carbonate,phosphate or tert-butoxy/phenoxy bases, such as K₂CO₃, K₃PO₄, Na₂CO₃,Cs₂CO₃, K(t-BuO), Na(t-BuO), K(OPh), Na(OPh), and tetraalkylammoniumsalts or mixtures thereof.

Preferred bases include K₂CO₃, Na₂CO₃ and Cs₂CO₃, of which Cs₂CO₃ ismost preferred.

The base is preferably present as 1 to 4 equivalents of the moiety offormula II, and more preferably as 1 to 1.5 or 2 equivalents.

Optional Additive

The reaction mixture may also contain an optional additive which acts asa fluoride source, to aid the progress of the reaction. Such fluoridesources include, but are not limited to, KF, CsF, tetrabutylammoniumfluoride, tris(diethylaminosulfonium difluorotrimethylsilicate (TASF)and tetrabutylammonium triphenyldifluorosilicate (TBAT), of which KF ismost preferred.

The optional additive is preferably present as 1 to 2 equivalents of themoiety of formula III, and more preferably as 1 to 1.3 or 1.5equivalents.

Labile Leaving Group

Labile leaving groups suitable for use in the present invention are inparticular those known to be amenable to palladium catalysed coupling.Suitable groups include mesylate (—OSO₂CH₃); —OSO₂(C_(n)F_(2n+1)), wheren=0-4; —OSO₂—R^(S), where R^(S) is an optionally substituted phenylgroup (e.g. 4-Me-Ph, tosylate); —N⁺Me₃X⁻, where X may be OTf, OTs, I,Br, Cl, OH; I, Br and Cl. More preferred are —OSO₂(C_(n)F_(2n+1)) wheren=0, 1 or 4 (in particular triflate), I, Br and Cl, with Br being themost preferred.

Amount of Compound of Formula III

When the moiety of formula III is not bound to the moiety of formula II,it is preferably present as 1 to 2 equivalents, and is more preferably 1to 1.3 or 1.5 equivalents, of the compound of formula II.

Reaction Temperature

The reaction is preferably carried out at room temperature (i.e. 20° C.)or higher, more preferably higher than 50° C., but at 200° C. or lower.A most preferred temperature range for the reaction is between 60° C.and 120° C., with temperatures of about 100° C. being particularlypreferred.

Substituents

The phrase “optionally substituted” as used herein, pertains to a parentgroup which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term “substituted” as used herein,pertains to a parent group which bears one or more substitutents. Theterm “substituent” is used herein in the conventional sense and refersto a chemical moiety which is covalently attached to, or if appropriate,fused to, a parent group. A wide variety of substituents are well known,and methods for their formation and introduction into a variety ofparent groups are also well known.

Examples of substituents are described in more detail below. C₁₋₇ alkyl:The term “C₁₋₇ alkyl” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from a carbon atom of a hydrocarboncompound having from 1 to 7 carbon atoms, which may be aliphatic oralicyclic, and which may be saturated or unsaturated (e.g. partiallyunsaturated, fully unsaturated). Thus, the term “alkyl” includes thesub-classes alkenyl, alkynyl, cycloalkyl, etc., discussed below.

Examples of saturated alkyl groups include, but are not limited to,methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl (C₅) hexyl (C₆)and heptyl (C₇)

Examples of saturated linear alkyl groups include, but are not limitedto, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl (C₄), n-pentyl(amyl) (C₅), n-hexyl (C₆) and n-heptyl (C₇).

Examples of saturated branched alkyl groups include iso-propyl (C₃),iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄), iso-pentyl (C₅), andneo-pentyl (C₅).

C₂₋₇ Alkenyl: The term “C₂₋₇ alkenyl” as used herein, pertains to analkyl group having one or more carbon-carbon double bonds.

Examples of unsaturated alkenyl groups include, but are not limited to,ethenyl (vinyl, —CH═CH₂), 1-propenyl (—CH═CH—CH₃), 2-propenyl (allyl,—CH—CH═CH₂), isopropenyl (1-methylvinyl, —C(CH₃)═CH₂), butenyl (C₄),pentenyl (C₅), and hexenyl (C₆).

C₂₋₇ alkynyl: The term “C₂₋₁₂ alkynyl” as used herein, pertains to analkyl group having one or more carbon-carbon triple bonds.

Examples of unsaturated alkynyl groups include, but are not limited to,ethynyl (ethinyl, —C≡CH) and 2-propynyl (propargyl, —CH₂—C≡CH).

C₃₋₇ cycloalkyl: The term “C₃₋₇ cycloalkyl” as used herein, pertains toan alkyl group which is also a cyclyl group; that is, a monovalentmoiety obtained by removing a hydrogen atom from an alicyclic ring atomof a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3to 7 carbon atoms, including from 3 to 7 ring atoms.

Examples of cycloalkyl groups include, but are not limited to, thosederived from:

-   -   saturated monocyclic hydrocarbon compounds: cyclopropane (C₃),        cyclobutane (C₄), cyclopentane (C₅) cyclohexane (C₆),        cycloheptane (C₇), methylcyclopropane (C₄), dimethylcyclopropane        (C₅), methylcyclobutane (C₅), dimethylcyclobutane (C₆),        methylcyclopentane (C₆), dimethylcyclopentane (C₇) and        methylcyclohexane (C₇);    -   unsaturated monocyclic hydrocarbon compounds: cyclopropene (C₃),        cyclobutene (C₄), cyclopentene (C₅), cyclohexene (C₆),        methylcyclopropene (C₄), dimethylcyclopropene (C₅),        methylcyclobutene (C₅), dimethylcyclobutene (C₆),        methylcyclopentene (C₆), dimethylcyclopentene (C₇) and        methylcyclohexene (C₇); and    -   saturated polycyclic hydrocarbon compounds: norcarane (C₇),        norpinane (C₇), norbornane (C₇).

C₃₋₂₀ heterocyclyl: The term “C₃₋₂₀ heterocyclyl” as used herein,pertains to a monovalent moiety obtained by removing a hydrogen atomfrom a ring atom of a heterocyclic compound, which moiety has from 3 to20 ring atoms, of which from 1 to 10 are ring heteroatoms. Preferably,each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ringheteroatoms.

In this context, the prefixes (e.g. C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆heterocyclyl”, as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.

Examples of monocyclic heterocyclyl groups include, but are not limitedto, those derived from:

N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole)(C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrroleor 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆),dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);

O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole(dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆),pyran (C₆), oxepin (C₇);

S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene) (C₅),thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);

O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);

O₃: trioxane (C₆);

N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline(C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);

N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole(C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆),dihydrooxazine (C₆), oxazine (C₆);

N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);

N₂O₁: oxadiazine (C₆);

O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,

N₁O₁S₁: oxathiazine (C₆).

Examples of substituted monocyclic heterocyclyl groups include thosederived from saccharides, in cyclic form, for example, furanoses (C₅),such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse,and pyranoses (C₆), such as allopyranose, altropyranose, glucopyranose,mannopyranose, gulopyranose, idopyranose, galactopyranose, andtalopyranose.

C₅₋₂₀ aryl: The term “C₅₋₂₀ aryl”, as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from an aromaticring atom of an aromatic compound, which moiety has from 3 to 20 ringatoms. Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g. C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆ aryl” as used herein,pertains to an aryl group having 5 or 6 ring atoms.

The ring atoms may be all carbon atoms, as in “carboaryl groups”.

Examples of carboaryl groups include, but are not limited to, thosederived from benzene (i.e. phenyl) (C₆), naphthalene (C₁₀), azulene(C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), naphthacene (C₁₈), andpyrene (C₁₆)

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indane (e.g. 2,3-dihydro-1H-indene) (C₉), indene (C₉),isoindene (C₉), tetraline (1,2,3,4-tetrahydronaphthalene (C₁₀),acenaphthene (C₁₂), fluorene (C₁₃), phenalene (C₁₃), acephenanthrene(C₁₅), and aceanthrene (C₁₆).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroaryl groups”. Examples of monocyclic heteroaryl groups include,but are not limited to, those derived from:

N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);

O₁: furan (oxole) (C₅);

S₁: thiophene (thiole) (C₅);

N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);

N₂O₁: oxadiazole (furazan) (C₅);

N₃O₁: oxatriazole (C₅);

N₁S₁: thiazole (C₅), isothiazole (C₅);

N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅),pyridazine (1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆) (e.g.,cytosine, thymine, uracil), pyrazine (1,4-diazine) (C₆);

N₃: triazole (C₅), triazine (C₆); and,

N₄: tetrazole (C₅).

Examples of heteroaryl which comprise fused rings, include, but are notlimited to:

-   -   C₉ (with 2 fused rings) derived from benzofuran (O₁),        isobenzofuran (O₁), indole (N₁), isoindole (N₁), indolizine        (N₁), indoline (N₁), isoindoline (N₁), purine (N₄) (e.g.,        adenine, guanine), benzimidazole (N₂), indazole (N₂),        benzoxazole (N₁O₁), benzisoxazole (N₁O₁), benzodioxole (O₂),        benzofurazan (N₂O₁), benzotriazole (N₃), benzothiofuran (S₁),        benzothiazole (N₁S₁), benzothiadiazole (N₂S);    -   C₁₀ (with 2 fused rings) derived from chromene (O₁), isochromene        (O₁), chroman (O₁), isochroman (O₁), benzodioxan (O₂), quinoline        (N₁), isoquinoline (N₁), quinolizine (N₁), benzoxazine (N₁O₁),        benzodiazine (N₂), pyridopyridine (N₂), quinoxaline (N₂),        quinazoline (N₂), cinnoline (N₂), phthalazine (N₂),        naphthyridine (N₂), pteridine (N₄);    -   C₁₁ (with 2 fused rings) derived from benzodiazepine (N₂);    -   C₁₃ (with 3 fused rings) derived from carbazole (N₁),        dibenzofuran (O₁), dibenzothiophene (S₁), carboline (N₂),        perimidine (N₂), pyridoindole (N₂); and,    -   C₁₄ (with 3 fused rings) derived from acridine (N₁), xanthene        (O₁), thioxanthene (S₁), oxanthrene (O₂), phenoxathiin (O₁S₁),        phenazine (N₂), phenoxazine (N₁O₁), phenothiazine (N₁S₁),        thianthrene (S₂), phenanthridine (N₁), phenanthroline (N₂),        phenazine (N₂).

The above groups, whether alone or part of another substituent, maythemselves optionally be substituted with one or more groups selectedfrom themselves and the additional substituents listed below.

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇ alkylgroup (also referred to as a C₁₋₇ alkoxy group, discussed below), aC₃₋₂₀ heterocyclyl group (also referred to as a C₃₋₂₀ heterocyclyloxygroup), or a C₅₋₂₀ aryl group (also referred to as a C₅₋₂₀ aryloxygroup), preferably a C₁₋₇ alkyl group.

Alkoxy: —OR, wherein R is an alkyl group, for example, a C₁₋₇ alkylgroup. Examples of C₁₋₇ alkoxy groups include, but are not limited to,—OMe (methoxy), —OEt (ethoxy), —O(nPr) (n-propoxy), —O(iPr)(isopropoxy), —O(nBu) (n-butoxy), —O(sBu) (sec-butoxy), —O(iBu)(isobutoxy), and —O(tBu) (tert-butoxy).

Acetal: —CH(OR¹) (OR²), wherein R¹ and R² are independently acetalsubstituents, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group, or, in thecase of a “cyclic” acetal group, R¹ and R², taken together with the twooxygen atoms to which they are attached, and the carbon atoms to whichthey are attached, form a heterocyclic ring having from 4 to 8 ringatoms. Examples of acetal groups include, but are not limited to,—CH(OMe)₂, —CH(OEt)₂, and —CH(OMe) (OEt).

Hemiacetal: —CH(OH) (OR¹), wherein R¹ is a hemiacetal substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of hemiacetal groupsinclude, but are not limited to, —CH(OH) (OMe) and —CH(OH) (OEt).

Ketal: —CR(OR¹) (OR²), where R¹ and R² are as defined for acetals, and Ris a ketal substituent other than hydrogen, for example, a C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably aC₁₋₇ alkyl group. Examples ketal groups include, but are not limited to,—C(Me) (OMe)₂, —C(Me) (OEt)₂, —C(Me) (OMe) (OEt), —C(Et) (OMe)₂, —C(Et)(OEt)₂, and —C(Et)(OMe) (OEt).

Hemiketal: —CR(OH) (OR¹), where R¹ is as defined for hemiacetals, and Ris a hemiketal substituent other than hydrogen, for example, a C₁₋₇alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of hemiacetal groups include,but are not limited to, —C(Me) (OH) (OMe), —C(Et) (OH) (OMe), —C(Me)(OH) (OEt), and —C(Et) (OH) (OEt).

Oxo (keto, -one): ═O.

Thione (thioketone): ═S.

Imino (imine): ═NR, wherein R is an imino substituent, for example,hydrogen, C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably hydrogen or a C₁₋₇ alkyl group. Examples of estergroups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.

Formyl (carbaldehyde, carboxaldehyde): —C(═O)H.

Acyl (keto): —C(═O)R, wherein R is an acyl substituent, for example, aC₁₋₇ alkyl group (also referred to as C₁₋₇ alkylacyl or C₁₋₇ alkanoyl),a C₃₋₂₀ heterocyclyl group (also referred to as C₃₋₂₀ heterocyclylacyl),or a C₅₋₂₀ aryl group (also referred to as C₅₋₂₀ arylacyl), preferably aC₁₋₇ alkyl group. Examples of acyl groups include, but are not limitedto, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃ (propionyl), —C(═O)C(CH₃)₃(t-butyryl), and —C(═O)Ph (benzoyl, phenone).

Carboxy (carboxylic acid): —C(═O)OH.

Thiocarboxy (thiocarboxylic acid): —C(═S)SH.

Thiolocarboxy (thiolocarboxylic acid): —C(═O)SH.

Thionocarboxy (thionocarboxylic acid): —C(═S)OH.

Imidic acid: —C(═NH)OH.

Hydroxamic acid: —C(═NOH)OH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,wherein R is an ester substituent, for example, a C₁₋₇ alkyl group, aC₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkylgroup. Examples of ester groups include, but are not limited to,—C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Examples of acyloxy groupsinclude, but are not limited to, —OC(═O)CH₃ (acetoxy), —OC(═O)CH₂CH₃,—OC(═O)C(CH₃)₃, —OC(═O) Ph, and —OC(═O)CH₂Ph.

Oxycarboyloxy: —OC(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of ester groups include,but are not limited to, —OC(═O)OCH₃, —OC(═O)OCH₂CH₃, —OC(═O)OC(CH₃)_(3,)and —OC(═O)OPh.

Amino: —NR¹R^(2,) wherein R¹ and R² are independently aminosubstituents, for example, hydrogen, a C₁₋₇ alkyl group (also referredto as C₁₋₇ alkylamino or di-C₁₋₇ alkylamino), a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇ alkyl group, or, inthe case of a “cyclic” amino group, R¹ and R², taken together with thenitrogen atom to which they are attached, form a heterocyclic ringhaving from 4 to 8 ring atoms. Amino groups may be primary (—NH₂),secondary (—NHR¹), or tertiary (—NHR¹R²), and in cationic form, may bequaternary (—⁺NR¹R²R³). Examples of amino groups include, but are notlimited to, —NH₂, —NHCH₃, —NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh.Examples of cyclic amino groups include, but are not limited to,aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino,and thiomorpholino.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): —C(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of amido groups include, but are not limited to,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

Thioamido (thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof amido groups include, but are not limited to, —C(═S)NH₂, —C(═S)NHCH₃,—C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.

Acylamido (acylamino): —NR¹C(═O)R², wherein R¹ is an amide substituent,for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group,or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇ alkyl group, and R²is an acyl substituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇alkyl group. Examples of acylamide groups include, but are not limitedto, —NHC(═O)CH₃, —NHC(═O)CH₂CH₃, and —NHC(═O)Ph. R¹ and R² may togetherform a cyclic structure, as in, for example, succinimidyl, maleimidyl,and phthalimidyl:

Aminocarbonyloxy: —OC(═O)NR¹R², wherein R¹ and R² are independentlyamino substituents, as defined for amino groups. Examples ofaminocarbonyloxy groups include, but are not limited to, —OC(═O)NH₂,—OC(═O)NHMe, —OC(═O)NMe₂, and —OC(═O) NEt₂.

Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently aminosubstituents, as defined for amino groups, and R¹ is a ureidosubstituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇alkyl group. Examples of ureido groups include, but are not limited to,—NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂, —NMeCONH₂,—NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and —NMeCONEt₂.

Guanidino: —NH—C(═NH)NH₂.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

Imino: ═NR, wherein R is an imino substituent, for example, for example,hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group. Examples of imino groupsinclude, but are not limited to, ═NH, ═NMe, and ═NEt.

Amidine (amidino): —C(═NR)NR₂, wherein each R is an amidine substituent,for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group,or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇ alkyl group. Examples ofamidine groups include, but are not limited to, —C(═NH)NH₂, —C(═NH)NMe₂,and —C(═NMe)NMe₂.

Nitro: —NO₂.

Nitroso: —NO.

Azido: —N₃.

Cyano (nitrile, carbonitrile): —CN.

Isocyano: —NC.

Cyanato: —OCN.

Isocyanato: —NCO.

Thiocyano (thiocyanato): —SCN.

Isothiocyano (isothiocyanato): —NCS.

Sulfhydryl (thiol, mercapto): —SH.

Thioether (sulfide): —SR, wherein R is a thioether substituent, forexample, a C₁₋₇ alkyl group (also referred to as a C₁₋₇ alkylthiogroup), a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably aC₁₋₇ alkyl group. Examples of C₁₋₇ alkylthio groups include, but are notlimited to, —SCH₃ and —SCH₂CH₃.

Disulfide: —SS—R, wherein R is a disulfide substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group (also referred to herein as C₁₋₇ alkyldisulfide). Examples of C₁₋₇ alkyl disulfide groups include, but are notlimited to, —SSCH₃ and —SSCH₂CH₃.

Sulfine (sulfinyl, sulfoxide): —S(═O)R, wherein R is a sulfinesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfine groups include, but are not limited to, —S(═O)CH₃ and—S(═O)CH₂CH₃.

Sulfone (sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group, including, for example, afluorinated or perfluorinated C₁₋₇ alkyl group. Examples of sulfonegroups include, but are not limited to, —S(═O)₂CH₃ (methanesulfonyl,mesyl), —S(═O)₂CF₃ (triflyl), —S(═O)₂CH₂CH₃ (esyl), —S(═O)₂C₄F₉(nonaflyl), —S(═O)₂CH₂CF₃ (tresyl), —S(═O)₂CH₂CH₂NH₂ (tauryl), —S(═O)₂Ph(phenylsulfonyl, besyl), 4-methylphenylsulfonyl (tosyl),4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl),4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).

Sulfinic acid (sulfino): —S(═O)OH, —SO₂H.

Sulfonic acid (sulfo): —S(═O)₂OH, —SO₃H.

Sulfinate (sulfinic acid ester): —S(═O)OR; wherein R is a sulfinatesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfinate groups include, but are not limited to, —S(═O)OCH₃(methoxysulfinyl; methyl sulfinate) and —S(═O)OCH₂CH₃ (ethoxysulfinyl;ethyl sulfinate).

Sulfonate (sulfonic acid ester): —S(═O)₂OR, wherein R is a sulfonatesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfonate groups include, but are not limited to, —S(═O)₂OCH₃(methoxysulfonyl; methyl sulfonate) and —S(═O)₂OCH₂CH₃ (ethoxysulfonyl;ethyl sulfonate).

Sulfinyloxy: —OS(═O)R, wherein R is a sulfinyloxy substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of sulfinyloxy groupsinclude, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

Sulfonyloxy: —OS(═O)₂R, wherein R is a sulfonyloxy substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of sulfonyloxy groupsinclude, but are not limited to, —OS(═O)₂CH₃ (mesylate) and—OS(═O)₂CH₂CH₃ (esylate).

Sulfate: —OS(═O)₂OR; wherein R is a sulfate substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfate groups include, butare not limited to, —OS(═O)₂OCH₃ and —SO(═O)₂OCH₂CH₃.

Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): —S(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of sulfamyl groups include, but are not limitedto, —S(═O)NH₂, —S(═O)NH(CH₃), —S(═O)N(CH₃)₂, —S(═O)NH(CH₂CH₃),—S(═O)N(CH₂CH₃)₂, and —S(═O)NHPh.

Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide):—S(═O)₂NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of sulfonamido groups include, butare not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂,—S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

Sulfamino: —NR¹S(═O)₂OH, wherein R¹ is an amino substituent, as definedfor amino groups. Examples of sulfamino groups include, but are notlimited to, —NHS(═O)₂OH and —N(CH₃)S(═O)₂OH.

Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfonamino substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfonamino groups include,but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfinamino substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfinamino groups include,but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

Phosphino (phosphine): —PR₂, wherein R is a phosphino substituent, forexample, —H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably —H, a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group.Examples of phosphino groups include, but are not limited to, —PH₂,—P(CH₃)₂, —P(CH₂CH₃)₂, —P(t-Bu)₂, and —P(Ph)₂.

Phospho: —P(═O)₂.

Phosphinyl (phosphine oxide): —P(═O)R₂, wherein R is a phosphinylsubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group or a C₅₋₂₀aryl group. Examples of phosphinyl groups include, but are not limitedto, —P(═O)(CH₃)₂, —P(═O) (CH₂CH₃)₂, —P(═O)(t-Bu)₂, and —P(═O)(Ph)₂.

Phosphonic acid (phosphono): —P(═O)(OH)₂.

Phosphonate (phosphono ester): —P(═O)(OR)₂, where R is a phosphonatesubstituent, for example, —H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably —H, a C₁₋₇ alkyl group, or aC₅₋₂₀ aryl group. Examples of phosphonate groups include, but are notlimited to, —P(═O)(OCH₃)₂, —P(═O)(OCH₂CH₃)₂, —P(═O)(O-t-Bu)₂, and—P(═O)(OPh)₂.

Phosphoric acid (phosphonooxy): —OP(═O)(OH)₂.

Phosphate (phosphonooxy ester): —OP(═O)(OR)₂, where R is a phosphatesubstituent, for example, —H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably —H, a C₁₋₇ alkyl group, or aC₅₋₂₀ aryl group. Examples of phosphate groups include, but are notlimited to, —OP(═O)(OCH₃)₂, —OP(═O)(OCH₂CH₃)₂, —OP(═O)(O-t-Bu)₂, and—OP(═O)(OPh)₂.

Phosphorous acid: —OP(OH)₂.

Phosphite: —OP(OR)₂, where R is a phosphite substituent, for example,—H, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably —H, a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group.Examples of phosphite groups include, but are not limited to,—OP(OCH₃)₂, —OP(OCH₂CH₃)₂, —OP(O-t-Bu)₂, and —OP(OPh)₂.

Phosphoramidite: —OP(OR¹)—NR² ₂, where R¹ and R² are phosphoramiditesubstituents, for example, —H, a (optionally substituted) C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably —H,a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group. Examples of phosphoramiditegroups include, but are not limited to, —OP(OCH₂CH₃)—N(CH₃)₂,—OP(OCH₂CH₃)—N(i-Pr)₂, and —OP(OCH₂CH₂CN)—N(i-Pr)₂.

Phosphoramidate: —OP(═O)(OR¹)—NR² ₂, where R¹ and R² are phosphoramidatesubstituents, for example, —H, a (optionally substituted) C₁₋₇ alkylgroup, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably —H,a C₁₋₇ alkyl group, or a C₅₋₂₀ aryl group. Examples of phosphoramidategroups include, but are not limited to, —OP(═O)(OCH₂CH₃)—N(CH₃)₂,—OP(═O)(OCH₂CH₃)—N(i-Pr)₂, and —OP(═O)(OCH₂CH₂CN)—N(i-Pr)₂.

Further Substituent Groups

Particular substituent groups of interest are ion-chelating groups offormula [—(CH₂CH₂O)_(n)CH₂CH₂OCH₃], [—O(CH₂CH₂O)_(n)OCH₃],[—(CH₂CH(R^(A))O)_(n)CH₂CH₂OCH₃] and [—O(CH₂CH(R^(A))O)_(n)OCH₃],wherein n is an integer from 0 to 10, preferably 2 to 10, morepreferably 2 to 4, and R^(A) is C₁₋₁₀ alkyl, preferably C₁₋₂ alkyl, andwherein the ion chelating groups comprise side chains in ologomeric orpolymeric structures.

The ion chelating side chains are based on the repeat unit [—OCH₂CH₂—].Side chain branching and/or the inclusion of[—OCH₂O—] repeat-units, areadvantageous to inhibit crystallisation after metal ion complexation.The side chains contain preferably 3 or more [—OCH₂CH₂—] and mostpreferably 3 units terminating in OR^(A)(R^(A)=C₁₋₁₀ alkyl, e.g. methyl)containing 4 oxygen atoms for cation chelation. Crown ethers may also bedesigned accordingly. Other side chain designs may be made according tothe specific need for cation binding. Alternative design features couldbe incorporated into monomers and polymers to favour anion binding.

These substituent groups are discussed in detail in Reference 32.

The Ar¹, Ar² and Ar³ groups as defined in Reference 32 are also ofinterest as R^(N1), R^(N2) and R^(N3) in the present invention.

Compounds of Formula II

These compounds are either commercially available, or may be readilysynthesised using known techniques.

Compounds of Formula III

Compounds of formula III:

can be synthesised from compounds of Formula 1:

by methods known in the art. The method chosen will depend on thebasicity of the amine of formula 1. Typically, the compound of formula 1will be reacted with a base in organic solvent and then a compound offormula 2 added:

For example, some of the silylamines used in the examples below wereprepared as follows from the free amine.

The silylamines where R^(N2) is sulfonyl were prepared as follows from amodified amine by heating with bis(trimethylsilyl)trifluoroacetamide(BSTFA).

The silylamines were purified by vacuum distillation. Once purified,their were handled under nitrogen at all times, and stored at −20° C.

If the desired compound of formula I is a tri-aryl amine, then thebi-aryl silyl amine of formula III, may itself be synthesised from abi-aryl amine made by the method of the present invention.

Further Preferences

The compounds of formula (I) may be oligomeric or polymeric in nature,as described in Reference 32. In particular, all of R^(N1), R^(N2) andR^(N3) may be substituted C₅₋₂₀ aryl, preferably phenyl, with one ofR^(N1), R^(N2) and R^(N3) being a side chain group, and the other two ofR^(N1), R^(N2) and R^(N3) being linked to form an oligomeric orpolymeric backbone.

In some embodiments R^(N1) and R^(N2) are not linked by a single bond.

R^(N1)

R^(N1) is, in some embodiments, preferably optionally substituted C₅₋₇aryl, more preferably optionally substituted phenyl.

R^(N2)

R^(N2) is preferably selected from optionally substituted C₅₋₂₀ aryl,optionally substituted C₅₋₂₀ heterocyclyl, and optionally substitutedsulfonyl. If R^(N2) is a sulfonyl group, then the sulfonyl substituentis preferably optionally substituted C₁₋₇ alkyl.

R^(N2) is more preferably selected from optionally substituted C₅₋₂₀aryl and optionally substituted C₅₋₂₀ heterocyclyl, with optionallysubstituted C₅₋₂₀ aryl (e.g. phenyl) being most preferred.

R^(N3)

RN³ is preferably selected from optionally substituted C₁₋₇ alkyl, C₃₋₂₀heterocylyl and C₅₋₂₀ aryl. If R^(N3) is selected from C₁₋₇ alkyl, it ispreferably C₁₋₄ alkyl, and most preferably methyl. If R^(N3) is selectedfrom C₅₋₂₀ aryl, it is preferably C₅₋₇ aryl, and most preferably phenyl.

R^(N2) and R^(N3)

When RN² and RN³ together with the nitrogen atom to which they areattached form optionally substituted nitrogen-containing C₃₋₂₀heterocyclyl or C₅₋₂₀ heteroaryl, they preferably form optionallysubstituted nitrogen-containing C₅₋₂₀ heterocylyl or heteroaryl (e.g.pyrrolyl, indolyl).

R¹, R² and R³

R¹, R² and R³ are preferably independently selected from optionallysubstituted C₁₋₇ alkyl, C₅₋₂₀ aryl, C₃₋₂ heterocyclyl and C₁₋₇ alkoxy,or two of R¹, R² and R³, together with the silicon atom to which theyare attached, may form a silicon containing C₅₋₇ heterocyclyl group. Itis more preferred that R¹, R² and R³ are independently selected fromoptionally substituted C₁₋₇ alkyl, C₅₋₂₀ aryl and C₃₋₂₀ heterocyclyl,with optionally substituted C₁₋₇ alkyl being most preferred.

Examples of preferred SiR¹R²R³ groups include TMS, TES, TIPS, TDDMS,TBDPS and 1-methylsilacyclobutane.

Optional Substituents

The optional substituents for R^(N1), R^(N2) and R^(N3) when they areC₅₋₂₀ aryl groups, for example phenyl, include, but are not limited to,C₁₋₇ alkyl, C₁₋₇ alkoxy and C₁₋₇ alkyl ester, of which, in someembodiments, C₁₋₇ alkoxy (e.g. OMe) and C₁₋₇ alkyl ester (e.g. COOMe)are preferred.

EXAMPLES

General Method

Flame dried cesium carbonate (228 mg, 0.7 mmol, 1.4 eq), aryl bromide(0.5 mmol), palladium acetate (2.8 mg, 0.012 mmol, 2.5 mol %) anddi-tert-butyl biphenylphosphine (7.5 mg, 0.025 mmol, 5 mol %) wereplaced in a 10 cm³ stainless steal cell and the cell sealed. The cellwas evacuated and refilled with nitrogen (three cycles). The silylamine(1.2 eq) was injected through the inlet port and the cell connected tothe CO₂ line and charged with CO₂ (99.9995%—further purified over anOxisor^(RTM) catalyst) to approximately 760 psi (volume ca. 1 cm³ liquidcarbon dioxide). The cell was heated to 100° C. and the pressureadjusted to the desired pressure by the addition of further CO₂. Thereagents were maintained at this temperature and pressure for thedesired time before the cell was allowed to cool to room temperature.The contents of the cell were vented into ethyl acetate (50 cm³), andonce atmospheric pressure had been reached, the cell was opened andwashed with further ethyl acetate (3×10 cm³). The combined organicfractions were filtered and concentrated in vacuo to furnish the crudematerial that was purified by flash column chromatography.

Example 1

The reaction was carried out as described in the general method.

(a) R═COOMe, R′═COOMe, 3000 psi, 17 hours: Yield 84%

(b) R═COOMe, R′═COOMe, 1800 psi, 17 hours: Yield 69%

(c) R═COOMe, R′═OMe, 3000 psi, 17 hours: Yield 40%

(d) R═COOMe, R′═OMe, 1800 psi, 48 hours: Yield 77%

(e) R═COOMe, R′═H, 3000 psi, 17 hours: Yield 28%

(f) R═COOMe, R′═H, 1800 psi, 48 hours: Yield 76%

(g) R═H, R′═COOMe, 1800 psi, 17 hours: Yield 77%

(h) R═H, R′═H, 1800 psi, 48 hours: Yield 55%

(i) R═H, R′═OMe, 1800 psi, 48 hours: Yield 66%

(j) R═OMe, R′═COOMe, 1800 psi, 17 hours: Yield 57%

(k) R═OMe, R′═H, 1800 psi, 48 hours: Yield 25%

(l) R═OMe, R′═OMe, 1800 psi, 48 hours: Yield 25%

As a comparison, the reaction was carried out with the same reagents intoluene, as follows. To an oven dried Schlenk tube under nitrogen wasadded cesium carbonate (228 mg, 0.7 mmol, 1.4 eq) and the cesiumcarbonate was flame dried under vacuum with stirring. Methylbromobenzoate (108 mg, 0.5 mmol), palladium acetate (5.6 mg, 0.024 mmol,5 mol %) and di-tert-butyl biphenylphosphine (15 mg, 0.05 mmol, 10 mol%) were added and the Schlenk tube sealed, and evacuated and refilledwith nitrogen (3 cycles). A solution of the silylamine (1.2 eq) in drytoluene (1.5 cm³) was added and the reaction mixture heated at 100° C.for the desired time. The reaction mixture was allowed to cool to roomtemperature. The mixture was filtered and concentrated in vacuo tofurnish the crude material which was purified by flash columnchromatography. The yields are shown in Table 1, with the time for eachexperiment in parentheses.

TABLE 1 R═COOMe R═H R═OMe R′═COOMe 66 (34 h) 41 (17 h) 63 (17 h) R′═H 65(54 h) 12 (17 h) 8 (17 h) R′═OMe 72 (54 h) 25 (17 h) 7 (17 h)

Example 2

The reaction was carried out as described in the general method, withthe R group and either the N-trimethylsilyl-pyrrole or indole as shownin Table 3, with the yields expressed in %. The reactions were carriedout at ca. 1800 psi for 17 hours. The catalyst ligand used was either:

wherein ligand A is that described in the general method.

TABLE 2 Yield (%) Substrate X A B Pyrrole COOMe 59 75 H 11 46 OMe 7 30Indole COOMe 70 88 H 68 70 OMe 25 50

Example 3

The reaction is carried out as described in the general method, whereinthe starting material is added at the silylamine stage. An additive (1.2eq) was sometimes added (see table 3) at the same time as the Cs₂CO₃.The reaction was carried out at 1800 psi for the length of time as shownin Table 3.

TABLE 3 R Additive Time (hours) Yield (%)

— 17 43

— 41 61

KF 41 57 —CH₃ — 17 55 —CH₃ — 41 28 —CH₃ KF 17 72

As a comparison, the reaction was also carried out where the startingmaterial did not bear the trimethyl silyl group, as shown in Table 4:

TABLE 4 R Additive Time (hours) Yield (%)

— 17 20 —CH₃ — 17 22

Example 4

The reaction is carried out as described in the general method, and anadditive (1.2 eq) was sometimes added (see table 5) at the same time asthe Cs₂CO₃. The reaction was carried out at 1800 psi for the length oftime as shown in Table 5.

TABLE 5 R R′ Additive Time (hours) Yield (%) —CH₃ COOMe — 17 15 —CH₃COOMe KF 17 56 —CH₃ COOMe KF 41 55

REFERENCE

(all of which Are Herein Incorporates by Reference)

-   (1) M. Stolka, J. F. Yanus, and D. M. Pai, J. Phys. Chem., 1984, 88,    4707-4714-   (2) E. Ueta, H. Nakano, and Y. Shirota, Chem. Lett., 1994, 2397.-   (3) Y. Kuwabara, H. Ogawa, H. Inada, N. Noma, and Y. Shirota, Adv.    Mater., 1994, 6, 677.-   (4) M. Strukelj, R. H. Jordan, and A. Dodabalapur, J. Am. Chem.    Soc., 1996, 118, 1213-1214.-   (5) A. Kitani, M. Kaya, J. Yano, K. Yoshikawa, and K. Sasaki, Synth.    Met., 1987, 18, 341-346.-   (6) F.-L. Lu, F. Wudl, M. Nowak, and A. J. Heeger, J. Am. Chem.    Soc., 1986, 108, 8311-13.-   (7) A. G. MacDiarmid, J. C. Chiang, A. F. Richter, and A. J.    Epstein, Synth. Met., 1987, 18, 285-290.-   (8) A. G. MacDiarmid, and A. J. Epstein, Faraday Discuss. Chem.    Soc., 1989, 88, 317-332.-   (9) A. G. MacDiarmid, and A. J. Epstein, Science and Applications of    Conducting Polymers; Hilger: New York, 1991.-   (10) A. Ray, A. F. Richter, D. L. Kershner, and A. J. Epstein,    Synth. Met., 1989, 29, 141-150.-   (11) D. Vachon, R. O. Angus, Jr., F.-L. Lu, M. Nowak, Z. X. Liu, H.    Schaffer, F. Wudl, and A. J. Heeger, Synth. Met., 1987, 18, 297-302.-   (12) R. S. Oakes, A. A. Clifford, and C. M. Rayner, J. Chem. Soc.    Perkin Trans 1, 2001, 917-941.-   (13) P. G. Jessop, and W. Leitner Chemical Synthesis Using    Supercritical Fluids; Wiley-VCH: Weinheim, 1999.-   (14) A. I. Cooper, Adv. Mater., 2001, 13, 1111-1114.-   (15) M. A. Carroll, and A. B. Holmes, Chem. Commun., 1998,    1395-1396.-   (16) T. R. Early, R. S. Gordon, M. A. Carroll, A. B. Holmes, R. E.    Shute, and I. F. McConvey, Chem. Commun., 2001, 1966-1967.-   (17) R. S. Gordon, and A. B. Holmes, Chem. Commun., 2002, 640-641.-   (18) S. V. Ley, C. Ramarao, R. S. Gordon, A. B. Holmes, A. J.    Morrison, I. F. McConvey, I. M. Shirley, S. C. Smith, and M. D.    Smith, Chem. Commun., 2002, 1134-1135.-   (19) N. Sundararajan, S. Yang, K. Ogino, S. Valiyaveettil, J. G.    Wang, X. Y. Zhou, C. K. Ober, S. K. Obendorf, and R. D. Allen, Chem.    Mater., 2000, 12, 41-48.-   (20) Y. C. Bae, K. Douki, T. Y. Yu, J. Y. Dai, D. Schmaljohann, H.    Koerner, C. K. Ober, and W. Conley, Chem. Mater., 2002, 14,    1306-1313.-   (21) J. M. D. E. Hoggan, R. G. Carbonell, Polym. Prepr. Am. Chem.    Soc. Div. PMSE, Part 2 Aug. 22, 1999, 218.-   (22) S. L. Wells, and J. DeSimone, Angew. Chem. Int. Ed. Engl.,    2001, 40, 518-527.-   (23) F. Gaspar, T. Lu, R. Santos, B. Al-Duri, A. B. Holmes, G.    Leeke, W. T. S. Huck, C. K. Luscombe, and J. Seville, Patterned    deposition using compressed carbon dioxide, 2003, EP 1 341 616.-   (24) J. Lindley, Tetrahedron, 1984, 40, 1433-1456.-   (25) H. L. Aalten, G. van Koten, and D. M. Grove, Tetrahedron, 1989,    45, 5565-5578.-   (26) A. J. Paine, J. Am. Chem. Soc., 1987, 109, 1496-1502.-   (27) H. Weingarten, J. Org. Chem., 1964, 29, 975-977.-   (28) S. L. Buchwald, and A. S. Guram, Preparation of arylamines,    1994, U.S. Pat. No. 5,576,460.-   (29) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, and S. L. Buchwald, Acc.    Chem. Res., 1998, 31, 805-818.-   (30) J. F. Hartwig, Angew. Chem. Int. Ed. Engl., 1998, 37,    2046-2047.-   (31) B. Yang, and S. L. Buchwald, J. Organometallic Chem., 1999,    576, 125-146; A. R. Muci and S. L. Buchwald in Topics in Current    Chemistry: Cross Coupling Reactions, Vol. 219, Springer-Verlag,    Berlin, 2002.-   (32) A. B. Holmes, and T. Park, Electroactive polyarylamine-type    compositions, 2002, WO 02/051958.-   (33) C. Salvatore, Light emissive polymer blends and light emissive    devices made from the same, 2003, EP 1 326 942.-   (34) J. J. M. Halls, C. A. Walsh, N. C. Greenham, E. A.    Marseglia, R. H. Friend, S. C. Moratti, and A. B. Holmes, Nature,    1995, 376, 498-500.-   (35) A. Fürstner, L. Ackermann, K. Beck, H. Hori, D. Kock, K.    Langermann, M. Liebl, C. Six, and W. Leitner, J. Am. Chem. Soc.,    2001, 123, 9000-9006.-   (36) A. B. Holmes, R. S. Gordon, and T. R. Early, WO 03/009936.-   (37) A. Baiker, Chem. Rev, 1999, 99, 453-474 (p. 455)-   (38) Shezad, N., Oakes, R. S., Clifford, A. A., and Rayner, C. M.,    Chemical Industries (Dekker) 2001, 82 (Catalysis of Organic    Reactions), 459-464-   (39) N. Shezad, A. A. Clifford, and C. M. Rayner, Green Chemistry    2002, 4(1), 64-67-   (40) WO96/01304-   (41) WO95/22591-   (42) WO94/20444-   (43) WO94/06738-   (44) EP 0 652 202-   (45) U.S. Pat. No. 6,156,933-   (46) Nolan, Ionic liquids as green solvents: progress and prospects,    ACS Symposium Series, 2003, 856, 323-341-   (47) A. Deagostino, C. Prandi and P. Venurello, Org. Lett., 2003, 5,    3815-3817-   (48) New Aspects in Phosphorus Chemistry II, Top. Curr. Chem., 2003,    223, 1-44

1. A method of synthesising a compound of formula I:

comprising the step of reacting a moiety of formula II:R^(N1)—L  (II) with a moiety of formula III:

in compressed carbon dioxide in the presence of a transition metalcatalyst and a base, wherein: L is a labile leaving group; R^(N1) isoptionally substituted C₅₋₂₀ aryl; R^(N2) is selected from optionallysubstituted C₅₋₂₀ aryl, optionally substituted C₃₋₂₀ heterocyclyl,optionally substituted C₃₋₇ alkyl, and optionally substituted sulfonyl;R^(N3) is selected from H and optionally substituted C₁₋₇ alkyl, C₃₋₂₀heterocyclyl and C₅₋₂₀ aryl; or R^(N2) and R^(N3) together with thenitrogen atom to which they are attached form optionally substitutednitrogen-containing C₃₋₂₀ heterocylyl or C₅₋₂₀ heteroaryl; and R¹, R²and R³ are independently selected from optionally substituted C₁₋₇alkyl, C₅₋₂₀ aryl, C₃₋₂₀ heterocyclyl, hydroxy, halo, amino and C₁₋₇alkoxy, or two of R¹, R² and R³, together with the silicon atom to whichthey are attached, may form a silicon containing C₅₋₇ heterocyclylgroup.
 2. A method according to claim 1, wherein the compressed carbondioxide is supercritical carbon dioxide.
 3. A method according to claim1, wherein the transition metal catalyst is a palladium catalyst.
 4. Amethod according to claim 3, wherein the palladium catalyst comprisesone or more phosphine ligands.
 5. A method according to claim 1, whereinthe base is selected from group 1 metal carbonate andtert-butoxy/phenoxy bases.
 6. A method according to claim 5, wherein thebase is Cs₂CO₃.
 7. A method according to claim 1, wherein a fluoridesource is present.
 8. A method according to claim 7, wherein thefluoride source is selected from KF and CsF.
 9. A method according toclaim 1, wherein the reaction is carried out at a temperature of between20 and 200° C.
 10. A method according to claim 1, wherein the labileleaving group is selected from I, Br, Cl and OSO₂CF₃.
 11. A methodaccording to claim 1, wherein R^(N2) is selected from optionallysubstituted C₅₋₂₀ aryl, optionally substituted C₅₋₂₀ heterocyclyl, andoptionally substituted sulfonyl.
 12. A method according to claim 1,wherein R^(N3) is selected from optionally substituted C₁₋₇ alkyl, C₃₋₂₀heterocylyl and C₅₋₂₀ aryl.
 13. A method according to claim 1, whereinR¹, R² and R³ are independently selected from optionally substitutedC₁₋₇ alkyl, C₅₋₂₀ aryl, C₃₋₂₀ heterocyclyl and C₁₋₇ alkoxy, or two ofR¹, R² and R³, together with the silicon atom to which they areattached, may form a silicon containing C₅₋₇ heterocyclyl group.